Jors, S.* ; Jeliazkova, P.* ; Ringelhan, M. ; Thalhammer, J.* ; Dürl, S.* ; Ferrer, J.* ; Sander, M.* ; Heikenwälder, M. ; Schmid, R.M.* ; Siveke, J.T.* ; Geisler, F.*
Lineage fate of ductular reactions in liver injury and carcinogenesis.
J. Clin. Invest. 125, 2445-2457 (2015)
Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.
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Publication type
Article: Journal article
Document type
Scientific Article
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Keywords
Hepatic Progenitor Cells; Biliary Epithelial-cells; Stem-cells; Mouse-liver; Hepatocellular-carcinoma; Mature Hepatocytes; Adult Hepatocytes; Oval Cells; In-vitro; Mice
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Language
english
Publication Year
2015
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2015
ISSN (print) / ISBN
0021-9738
e-ISSN
1558-8238
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Volume: 125,
Issue: 6,
Pages: 2445-2457
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American Society of Clinical Investigation
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Ann Arbor
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Reviewing status
Peer reviewed
POF-Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s)
Immune Response and Infection
PSP Element(s)
G-551600-001
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Erfassungsdatum
2015-05-08